Citation: Hou Guige, Jiang Chengshi, Liu Hongchun, Tong Linjiang, Peng Xia, Ji Yinchun, Geng Meiyu, Xiao Wei, Gong Jingxu, Guo Yuewei. Synthesis and Activity Evaluation of Novel 3, 4-Dihydro-benzo[b]-oxazepin-5(2H)-one Derivatives as Protein Kinases Inhibitors[J]. Chinese Journal of Organic Chemistry, ;2017, 37(6): 1463-1472. doi: 10.6023/cjoc201611005 shu

Synthesis and Activity Evaluation of Novel 3, 4-Dihydro-benzo[b]-oxazepin-5(2H)-one Derivatives as Protein Kinases Inhibitors

Hou Guige ^a,b,† ,
Jiang Chengshi ^a,c,† ,
Liu Hongchun ^a ,
Tong Linjiang ^a ,
Peng Xia ^a ,
Ji Yinchun ^a ,
Geng Meiyu ^a ,
Xiao Wei ^d,*,, ,
Gong Jingxu ^a,*,, ,
Guo Yuewei ^a

a.
State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203
b.
Key Laboratory of Prescription Effect and Clinical Evaluation of State Administration of Traditional Chinese Medicine of China, Binzhou Medical University, Yantai 264003
c.
School of Biological Science and Technology, Jinan University, Jinan 250022
d.
Jiangsu Kanion Pharmaceutical Co. Ltd, Lianyungang 222001

Corresponding author: Xiao Wei, wzhzh-nj@163.net Gong Jingxu, jxgong@mail.shcnc.ac.cn
Received Date: 2 November 2016
Revised Date: 9 January 2017

Fund Project: the National Natural Science Foundation of China 81520108028Shanghai Science and Technology Committee Project 14431901100the National Natural Science Foundation of China 21402010the National Natural Science Foundation of China 81273430the National Natural Science Foundation of China 81302692the National Natural Science Foundation of China 8160131016the National Natural Science Foundation of China 41476063the National Natural Science Foundation of China 21672230the National Natural Science Foundation of China 41506187the Institutes for Drug Discovery and Development, Chinese Academy of Sciences CASIMM0120152039the National Natural Science Foundation of China-Shandong Joint Fund for Marine Science Research Centers U1406402the National Natural Science Foundation of China 4167060562the Shanghai Science and Technology Committee Project 15431901000the State Key Laboratory of Drug Research/Shanghai Institute of Materia Medica Projects SIMM1501ZZ-03

Figures(3)

A series of novel 3, 4-dihydro-benzo[b]oxazepin-5(2H)-one derivatives were designed and synthesized as potent protein-tyrosine kinases (PTKs, e.g. ErbB1, ErbB2, c-Met, ALK, FGFR1, RET, KDR) inhibitors. All compounds were characterized by NMR and MS. E-7-[(2, 5-dihydroxy)phenylmethylene]amino-3, 4-dihydro-benzo[b]oxazepin-5(2H)-one (8k) and E-7-[(2, 3, 4-trihydroxy)phenylmethylene]amino-3, 4-dihydro-benzo[b]oxazepin-5(2H)-one (8n) were further characterized by X-ray single-crystal analysis. The synthesized compounds were further tested for their inhibitory activity on PTKs. The results display compounds with catechol-substitution display the most potent inhibitory activities toward PTKs. The IC₅₀ values for E-7-[(3, 4-dihydroxy)phenylmethylene]amino-3, 4-dihydro-benzo[b]oxazepin-5(2H)-one (8i) against ErbB1, ErbB2 are 1.0 and 0.33 μmol/L, respectively. The IC₅₀ value for 8n against RET is 0.7 μmol/L, while the IC₅₀ value for 7-[(3, 4-dihydroxyphenyl)methyl]amino-2, 3, 4, 5-tetrahydro-benzo[b]oxazepin-5-ol (10b) against ErbB2 is 1.02 μmol/L.
- 3, 4-dihydro-benzo[b]oxazepin-5(2H)-one derivatives,
- synthesis,
- protein-tyrosine kinases inhibitors,
- ErbB1,
- ErbB2
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